Aqueous ophthalmic composition comprising diquafosol or salt thereof and polyvinylpyrrolidone

Abstract

To provide an aqueous ophthalmic composition capable of reducing side effects, such as eye irritation, while enhancing the medicinal effect of diquafosol or a salt thereof.SOLUTION: Specifically, the aqueous ophthalmic composition for the prevention or treatment of dry eye comprises diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone with a K value of 90, and silver nitrate and is given 1 to 2 drops at a time, 2 to 4 times a day. The aqueous ophthalmic composition for the prevention or treatment of dry eye comprises diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone, and silver nitrate, has a viscosity of 3-30 mPa-s at 25°C, and is given 1 to 2 drops at a time, 2 to 4 times a day.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone. [Background technology]

[0002] Jikuahosol is P 1 ,P 4 - Di(uridine-5')tetraphosphate, or Up4U, is a purinergic receptor agonist that promotes lacrimal secretion. Its salt, diquafosol sodium, is also known as "Diquafosol." (登録商標) Eye Drops 3% (hereinafter referred to as "Diquas (登録商標) It is used as an eye drop to treat dry eye (Patent No. 3652707 (Patent Document 1), Diquas (登録商標) Eye drops 3% Package insert (Non-patent document 1)). (登録商標) The usual dosage of eye drops is one drop at a time, six times a day (Non-Patent Document 1), but there are severe dry eye patients who do not achieve sufficient therapeutic effects even when using the prescribed dosage. Furthermore, in daily life, it can be difficult to apply eye drops regularly and frequently, and there are also patients who do not achieve the expected effects due to poor adherence to eye drops. In addition, although it is rare, Diquas (登録商標) Some patients complain of side effects such as eye irritation when using eye drops (Non-Patent Document 1).

[0003] In an attempt to search for a new dry eye treatment agent with a higher tear volume increasing effect, it is known to use diquafosol or its salt in combination with an existing dry eye treatment agent. JP 2012-077080 A (Patent Document 2) discloses that the combined use of diquafosol or its salt and hyaluronic acid, a dry eye treatment agent, synergistically promotes tear secretion. JP 2015-160826 A (Patent Document 3) discloses that the combined use of diquafosol or its salt and rebamipide, a dry eye treatment agent, synergistically promotes tear secretion. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3652707 [Patent Document 2] JP 2012-077080 A [Patent Document 3] JP 2015-160826 A [Non-patent literature]

[0005] [Non-Patent Document 1] Diquas (registered trademark) eye drops 3% package insert Summary of the Invention [Problem to be solved by the invention]

[0006] It is an interesting problem to provide an aqueous ophthalmic composition that can enhance the medicinal efficacy of diquafosol or a salt thereof while reducing side effects such as eye irritation. [Means for solving the problem]

[0007] As a result of intensive research, the present inventors have found that an aqueous ophthalmic composition containing diquafosol or a salt thereof and polyvinylpyrrolidone (hereinafter also referred to as "the composition") exhibits a significant improvement in fluorescein staining score, i.e., a significant effect of improving corneal epithelial damage, and have clarified that polyvinylpyrrolidone enhances the efficacy of diquafosol or a salt thereof. In addition, the present inventors have found that the composition, which has a certain viscosity due to the inclusion of polyvinylpyrrolidone having a certain K value, has a certain viscosity compared to existing diquafosol. (登録商標) Less than eye drops No instillation times with existing Diquas (登録商標)It has also been found that the composition has a therapeutic effect equal to or greater than that of eye drops. It has also been found that the composition exhibits high cell viability and is highly safe for the corneal and conjunctival epithelium. It has also been found that the composition does not exhibit nerve irritation and can further improve the feeling of application of eye drops. Furthermore, it has also been found that even if the composition contains a silver salt, the silver salt is stable and the composition containing the silver salt exhibits excellent preservative efficacy.

[0008] That is, the present invention relates to the following.

[0009] (1) An aqueous ophthalmic composition comprising diquafosol or a salt thereof, and polyvinylpyrrolidone.

[0010] (2) The aqueous ophthalmic composition according to (1), further comprising a silver salt.

[0011] (3) The aqueous ophthalmic composition according to (2), wherein the silver salt comprises silver nitrate.

[0012] (4) The aqueous ophthalmic composition according to any one of (1) to (3) for preventing or treating dry eye.

[0013] (5) The aqueous ophthalmic composition according to (4), comprising diquafosol sodium at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone with a K value of more than 30 and not more than 120.

[0014] (6) The aqueous ophthalmic composition according to (4), comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of more than 30 and less than 120.

[0015] (7) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 1 to 5% (w / v) and has a viscosity of 1.5 to 30 mPa s at 25° C.

[0016] (8) The aqueous ophthalmic composition according to (4), which contains diquafosol sodium at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa s at 25° C.

[0017] (9) The aqueous ophthalmic composition according to any one of (5) to (8), which is administered by instillation into the eyes two to four times a day.

[0018] (10) The aqueous ophthalmic composition according to any one of (5) to (8), which is administered by instillation into the eye three times a day.

[0019] (11) The aqueous ophthalmic composition according to (9) or (10), wherein the composition is administered by instillation in the form of 1 to 2 drops at a time.

[0020] (12) An ophthalmologist's medicinal product, comprising 0.1 to 1 mL of the aqueous ophthalmic composition according to (1) filled in a unit-dose eye dropper container.

[0021] (13) An ophthalmologist's medicinal product, comprising 0.3 to 0.5 mL of the aqueous ophthalmic composition according to (1) filled in a unit-dose eye dropper container.

[0022] (14) An ophthalmic medicinal product, comprising 1 to 10 mL of the aqueous ophthalmic composition according to any one of (1) to (3) filled in a multi-dose eye drop container.

[0023] (15) An ophthalmic medicinal product, comprising 5 mL of the aqueous ophthalmic composition according to any one of (1) to (3) filled in a multi-dose eye drop container.

[0024] (16) An ophthalmic medicinal product, comprising 1 to 10 mL of the aqueous ophthalmic composition according to (1) filled in a PFMD container.

[0025] (17) An ophthalmic medicinal product, characterized in that 5 mL of the aqueous ophthalmic composition described in (1) is filled in a PFMD container.

[0026] (18) An ophthalmic medicinal product according to any one of (12) to (17) for preventing or treating dry eye.

[0027] (19) The ophthalmic medicinal product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone having a K value of more than 30 and less than or equal to 120.

[0028] (20) The ophthalmic medicinal product according to (18), wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of more than 30 and less than or equal to 120.

[0029] (21) The ophthalmic medicinal product according to (18), wherein the aqueous composition contains diquafosol sodium at a concentration of 1 to 5% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

[0030] (22) The ophthalmic medicinal product according to (18), wherein the aqueous composition contains diquafosol sodium at a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

[0031] (23) The ophthalmic medicinal product according to any one of (19) to (22), which is administered by instillation into the eyes 2 to 4 times a day.

[0032] (24) The ophthalmic medicinal product according to any one of (19) to (22), which is administered by instillation into the eyes three times a day.

[0033] (25) The ophthalmic medicinal product according to (23) or (24), characterized in that it is administered by instillation in the form of 1 to 2 drops at a time.

[0034] (26) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone having a K value of 17 or more.

[0035] (27) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone having a K value of 17 to 120.

[0036] (28) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone having a K value of more than 30 and not more than 120.

[0037] (29) The aqueous ophthalmic composition according to any one of (1) to (4), comprising polyvinylpyrrolidone having a K value of 90.

[0038] (30) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the concentration of the polyvinylpyrrolidone is 0.001% (w / v) or more.

[0039] (31) The concentration of the diquafosol or a salt thereof is 0.0001 to 10% (w / v). The aqueous ophthalmic composition according to any one of (1) to (4).

[0040] (32) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the diquafosol or a salt thereof has a concentration of 0.01 to 5% (w / v).

[0041] (33) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the diquafosol or a salt thereof has a concentration of 1 to 5% (w / v).

[0042] (34) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the diquafosol or a salt thereof has a concentration of 3% (w / v).

[0043] (35) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the aqueous ophthalmic composition has a pH in the range of 6 to 8.

[0044] (36) The aqueous ophthalmic composition according to any one of (1) to (11), wherein the aqueous ophthalmic composition has a pH in the range of 7 to 8.

[0045] (37) The aqueous ophthalmic composition according to any one of (1) to (11), which is a sterile aqueous eye drop.

[0046] (38) The aqueous ophthalmic composition according to any one of (1) to (11), which can be stored at room temperature.

[0047] (39) The aqueous ophthalmic composition according to any one of (1) to (6), wherein the aqueous ophthalmic composition has a viscosity of 1.5 to 30 mPa s at 25° C.

[0048] (40) The aqueous ophthalmic composition according to any one of (1) to (4), wherein the salt of diquafosol is diquafosol sodium.

[0049] (41) An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, characterized in that the composition is administered by instillation, 1 to 2 drops at a time, 2 to 4 times a day.

[0050] (42) An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone and silver nitrate, characterized in that the aqueous ophthalmic composition is administered by instillation of 1 to 2 drops at a time, 2 to 4 times a day, and has a viscosity of 3 to 30 mPa s at 25°C.

[0051] (43) The aqueous ophthalmic composition according to (41) or (42), which is administered by instillation into the eye three times a day.

[0052] (44) An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a unit-dose eye drop container filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, wherein the aqueous ophthalmic composition is administered by instillation in the eyes, 1 to 2 drops at a time, 2 to 4 times a day.

[0053] (45) An ophthalmic medicinal product for preventing or treating dry eye, comprising 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone filled in a unit dose type eye drop container, wherein the aqueous ophthalmic composition is An ophthalmic medicinal product characterized by having a viscosity of 3 to 30 mPa·s at 25°C and being administered by instillation in the eyes at a dose of 1 to 2 drops, 2 to 4 times a day.

[0054] (46) An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a multi-dose eye drop container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, wherein the aqueous ophthalmic composition is administered by instillation in the eyes, 1 to 2 drops at a time, 2 to 4 times a day.

[0055] (47) An ophthalmologist's medicinal product for the prevention or treatment of dry eye, comprising a multi-dose eye drop container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa s at 25°C and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

[0056] (48) An ophthalmologist's medicinal product for the prevention or treatment of dry eye, comprising a PFMD container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, wherein the aqueous ophthalmic composition is administered by instillation in the eyes, 1 to 2 drops at a time, 2 to 4 times a day.

[0057] (49) An ophthalmologist's medicinal product for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone filled in a PFMD container, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa s at 25°C and is used by instilling 1 to 2 drops at a time, 2 to 4 times a day.

[0058] (50) The ophthalmic medicinal product according to any one of (44) to (49), which is administered by instillation into the eyes three times a day.

[0059] (51) An ophthalmic medicinal product according to any one of (46) or (47), further comprising silver nitrate.

[0060] The present invention also relates to the following:

[0061] (A-1) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a unit-dose eye drop container at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and the unit-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

[0062] (A-2) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a unit-dose eye drop container at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) and has a viscosity of 3 to 30 mPa s at 25°C, and the unit-dose eye drop container is filled with 0.1 to 1 mL of the aqueous ophthalmic composition.

[0063] (A-3) A method for treating dry eye, comprising administering 1 to 2 drops of an aqueous ophthalmic composition filled in a multi-dose eye drop container to a patient 2 to 4 times a day, the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and the multi-dose eye drop container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0064] (A-4) A method for treating dry eye, comprising administering to a patient 1 to 2 drops of an aqueous ophthalmic composition filled in a multi-dose eye drop container at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) and has a viscosity of 3 to 30 mPa s at 25°C, and the multi-dose eye drop container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0065] (A-5) A method for treating dry eye, comprising administering 1 to 2 drops of an aqueous ophthalmic composition filled in a PFMD container to a patient at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0066] (A-6) A method for treating dry eye, comprising administering 1 to 2 drops of an aqueous ophthalmic composition filled in a PFMD container to a patient at a time, 2 to 4 times a day, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v) and has a viscosity of 3 to 30 mPa s at 25°C, and the PFMD container is filled with 1 to 10 mL of the aqueous ophthalmic composition.

[0067] (A-7) A method for treating dry eye according to any one of (A-1) to (A-6), comprising administering 1 to 2 drops of the aqueous ophthalmic composition to a patient three times a day.

[0068] (B-1) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, comprising 0.1 to 1 mL of an aqueous ophthalmic composition filled in a unit-dose eye dropper container, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and is administered by instillation of 1 to 2 drops at a time, 2 to 4 times a day.

[0069] (B-2) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, comprising 0.1 to 1 mL of an aqueous ophthalmic composition filled in a unit-dose eye dropper container, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v), has a viscosity of 3 to 30 mPa s at 25°C, and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

[0070] (B-3) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a multi-dose eye dropper container, wherein the aqueous ophthalmic composition contains diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

[0071] (B-4) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a multi-dose eye dropper container, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v), has a viscosity of 3 to 30 mPa s at 25°C, and is administered by instillation in the form of 1 to 2 drops at a time, 2 to 4 times a day.

[0072] (B-5) 1 to 10 mL of an aqueous ophthalmic composition for use in the prevention or treatment of dry eye an ophthalmic medicinal product comprising the aqueous ophthalmic composition filled in a PFMD container, the aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, and being administered by instillation in the eyes of 1 to 2 drops at a time, 2 to 4 times a day.

[0073] (B-6) An ophthalmologist's medicinal product used for the prevention or treatment of dry eye, comprising 1 to 10 mL of an aqueous ophthalmic composition filled in a PFMD container, wherein the aqueous ophthalmic composition contains diquafosol sodium and polyvinylpyrrolidone at a concentration of 3% (w / v), has a viscosity of 3 to 30 mPa s at 25°C, and is administered by instillation of 1 to 2 drops at a time, 2 to 4 times a day.

[0074] (B-7) The ophthalmic medicinal product according to any one of (B-1) to (B-6), characterized in that the aqueous ophthalmic composition is administered by instillation into the eye, 1 to 2 drops at a time, three times a day.

[0075] (C-1) Use of an aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, for the manufacture of a medicament for preventing or treating dry eye, wherein 0.1 to 1 mL of the aqueous ophthalmic composition is filled in a unit-dose eye drop container and used so that 1 to 2 drops are administered by instillation 2 to 4 times a day.

[0076] (C-2) Use of an aqueous ophthalmic composition for the manufacture of a medicament for preventing or treating dry eye, the aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa s at 25°C, wherein 0.1 to 1 mL of the aqueous ophthalmic composition is filled in a unit-dose eye drop container and used so that 1 to 2 drops are administered by instillation 2 to 4 times a day.

[0077] (C-3) Use of an aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, for the manufacture of a medicament for preventing or treating dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled in a multi-dose eye drop container and used so that 1 to 2 drops are administered by instillation 2 to 4 times a day.

[0078] (C-4) Use of an aqueous ophthalmic composition for the manufacture of a medicament for preventing or treating dry eye, the aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa s at 25°C, wherein 1 to 10 mL of the aqueous ophthalmic composition is filled in a multi-dose eye drop container and used so that 1 to 2 drops are administered by instillation 2 to 4 times a day.

[0079] (C-5) Use of an aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, for the manufacture of a medicament for the prevention or treatment of dry eye, characterized in that 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and used to be administered by instillation, 1 to 2 drops at a time, 2 to 4 times a day.

[0080] (C-6) Use of an aqueous ophthalmic composition for the manufacture of a medicament for preventing or treating dry eye, the aqueous ophthalmic composition comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone and having a viscosity of 3 to 30 mPa s at 25°C, wherein 1 to 10 mL of the aqueous ophthalmic composition is filled into a PFMD container and used so that 1 to 2 drops are administered by instillation 2 to 4 times a day.

[0081] (C-7) Use of the aqueous ophthalmic composition according to any one of (C-1) to (C-6), characterized in that the aqueous ophthalmic composition is administered by instillation into the eye, 1 to 2 drops at a time, three times a day.

[0082] (D-1) A method for imparting preservative efficacy to an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone, the method comprising incorporating a silver salt into the aqueous ophthalmic composition.

[0083] (D-2) A method for maintaining the preservative effectiveness of an aqueous ophthalmic composition containing diquafosol or a salt thereof, and polyvinylpyrrolidone, the method comprising incorporating a silver salt into the aqueous ophthalmic composition.

[0084] It should be noted that any two or more of the configurations of the present invention described above can be selected and combined. Effect of the Invention

[0085] This composition has a high tear volume increasing effect, so it is more effective than the existing Diquas (登録商標) Compared with the case where an eye drop is administered by instillation, the present composition is expected to have a stronger therapeutic effect on dry eye. (登録商標) It is expected that the drug will have the same or better therapeutic effect on dry eye as eye drops at a lower concentration. (登録商標) Eye drops need to be instilled six times a day, and there are patients who do not achieve the expected effect due to poor adherence to instillation. However, this composition, which has a certain viscosity due to the inclusion of polyvinylpyrrolidone with a certain K value, is more effective than existing Diquas eye drops. (登録商標) It can be instilled less frequently than conventional eye drops. (登録商標) Since it has therapeutic effects equivalent to or greater than those of eye drops, it is expected to improve adherence to eye drops.

[0086] Furthermore, the composition is expected to exhibit high cell viability, be highly safe for the corneal and conjunctival epithelium, exhibit no nerve irritation, and improve the comfort of eye drops when applied.

[0087] Furthermore, even if the composition contains a silver salt, the silver salt is stable and exhibits excellent preservative effectiveness. [Brief description of the drawings]

[0088] [Figure 1] 1 is a graph showing corneal fluorescein staining scores. [Diagram 2] FIG. 1 shows the results of a cytotoxicity test using corneal epithelial cells. [Diagram 3] FIG. 1 shows the maximum fluorescence intensity (RFUmax) after addition of diquafosol sodium. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0089] The present invention will now be described in further detail.

[0090] As used herein, "(w / v)%" refers to the mass (g) of the target component contained in 100 mL of the aqueous ophthalmic composition of the present invention.

[0091] As used herein, "PVP" means polyvinylpyrrolidone.

[0092] As used herein, "HEC" means hydroxyethyl cellulose.

[0093] As used herein, "CMC-Na" means sodium carboxymethylcellulose.

[0094] As used herein, "HPMC" means hydroxypropyl methylcellulose .

[0095] As used herein, "CVP" means carboxyvinyl polymer.

[0096] As used herein, "diquafosol ophthalmic solution" means an aqueous ophthalmic solution containing diquafosol or a salt thereof.

[0097] As used herein, "diquafosol sodium ophthalmic solution" means an aqueous ophthalmic solution containing diquafosol sodium.

[0098] "Diquafosol" is a compound represented by the following chemical structural formula.

[0099] [ka]

[0100] The "salt of diquafosol" is not particularly limited as long as it is a medicamentously acceptable salt, and examples thereof include metal salts with lithium, sodium, potassium, calcium, magnesium, zinc, and the like; salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; salts with acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, Examples of the salts include salts with organic acids such as p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, and sulfosalicylic acid; quaternary ammonium salts with methyl bromide and methyl iodide; salts with halogen ions such as bromide ion, chloride ion, and iodide ion; salts with ammonia; and salts with organic amines such as triethylenediamine, 2-aminoethanol, 2,2-iminobis(ethanol), 1-deoxy-1-(methylamino)-2-D-sorbitol, 2-amino-2-(hydroxymethyl)-1,3-propanediol, procaine, and N,N-bis(phenylmethyl)-1,2-ethanediamine.

[0101] In the present invention, "diquafosol or a salt thereof" also includes hydrates and organic solvates of diquafosol (free form) or a salt thereof.

[0102] When "diquafosol or a salt thereof" has a crystal polymorph or a crystal polymorphic group (crystal polymorphic system), the crystal polymorph or crystal polymorphic group (crystal polymorphic system) is also included in the scope of the present invention. Here, the crystal polymorphic group (crystal polymorphic system) refers to the preparation of those crystals. This refers to the individual crystal forms at each stage when the crystal form changes depending on the conditions and states such as crystallization, crystallization, and storage, as well as the entire process.

[0103] The "diquafosol or a salt thereof" of the present invention is preferably a sodium salt of diquafosol, and diquafosol tetrasodium salt (also simply referred to as "diquafosol sodium" in this specification) represented by the following chemical structural formula is particularly preferable.

[0104] [ka]

[0105] Diquafosol or a salt thereof can be produced by the method disclosed in JP-A-2001-510484, for example.

[0106] The composition may contain an active ingredient other than diquafosol or a salt thereof, or may contain diquafosol or a salt thereof as the only active ingredient.

[0107] In the present invention, the concentration of diquafosol or a salt thereof is not particularly limited, but is, for example, preferably 0.0001 to 10% (w / v), more preferably 0.001 to 5% (w / v), even more preferably 0.01 to 5% (w / v), even more preferably 0.1 to 5% (w / v), still more preferably 1 to 5% (w / v), and particularly preferably 3% (w / v). More specifically, 0.001%(w / v), 0.002%(w / v), 0.003%(w / v), 0.004%(w / v), 0.005%(w / v), 0.006%(w / v), 0.007%(w / v), 0.008% (w / v), 0.009%(w / v), 0.01%(w / v), 0.02%(w / v), 0.03%(w / v), 0.04%(w / v), 0.05%(w / v), 0.06%(w / v), 0.07%(w / v), 0.0 8%(w / v), 0.09%(w / v), 0.1%(w / v), 0.2%(w / v), 0.3%(w / v), 0.4%(w / v), 0.5%(w / v), 0.6%(w / v), 0.7%(w / v), 0.8%(w / v) , 0.9% (w / v), 1% (w / v), 1.5% (w / v), 2% (w / v), 2.5% (w / v), 3% (w / v), 3.5% (w / v), 4% (w / v), 4.5% (w / v) or 5% (w / v) are preferred.

[0108] In the present invention, "polyvinylpyrrolidone" refers to a polymer compound obtained by polymerization of N-vinyl-2-pyrrolidone, and is generally used as a thickening agent. Polyvinylpyrrolidone is also called povidone. The K value of the polyvinylpyrrolidone used in the present invention is preferably 17 or more, more preferably 17 to 120, even more preferably 25 to 120, and most preferably 30 to 120. More preferably, it is more than 30 and not more than 120, even more preferably 40 to 120, even more preferably 60 to 120, particularly preferably 60 to 90, and even more particularly preferably 90. Examples include polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, polyvinylpyrrolidone K30, polyvinylpyrrolidone K40, polyvinylpyrrolidone K50, polyvinylpyrrolidone K60, polyvinylpyrrolidone K70, polyvinylpyrrolidone K80, polyvinylpyrrolidone K85, polyvinylpyrrolidone K90, and polyvinylpyrrolidone K120. The K value of polyvinylpyrrolidone is a viscosity characteristic value that correlates with the molecular weight, and is a value calculated by applying the relative viscosity value (25°C) measured by a capillary viscometer to the following Fikentscher formula (1).

[0109]

number

[0110] In formula (1), η rel is the relative viscosity of the aqueous polyvinylpyrrolidone solution to water, and c is the concentration (%) of polyvinylpyrrolidone in the aqueous polyvinylpyrrolidone solution.

[0111] Here, the K value is 90 to 108% of the indicated K value in accordance with the description of the K value in the Japanese Pharmacopoeia, 17th Edition, for "Povidone." For example, "K90" refers to a viscosity characteristic value (K value) calculated by applying the above formula (1) in the range of 81 to 97.2.

[0112] In the present invention, the polyvinylpyrrolidone may be used alone, or two or more kinds of polyvinylpyrrolidones having different K values ​​may be used in any combination.

[0113] In the present invention, the concentration of polyvinylpyrrolidone is not particularly limited, and may be, for example, 0.001% (w / v) or more, preferably 0.001 to 10% (w / v), more preferably 0.01 to 10% (w / v), even more preferably 0.05 to 10% (w / v), still more preferably 0.1 to 10% (w / v), particularly preferably 0.1 to 5% (w / v), and particularly preferably 1 to 5% (w / v).

[0114] The composition may further contain a pharma- ceutically acceptable preservative if necessary, such as silver salts such as silver nitrate, benzalkonium chloride, benzalkonium bromide, benzethonium chloride, chlorhexidine gluconate, boric acid, borax, sorbic acid, potassium sorbate, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, polydronium chloride, polyhexanide hydrochloride, etc.

[0115] As is clear from the test results described below, the present composition containing a silver salt has excellent preservative effect, and therefore the preferred preservative in the present invention is a silver salt. Examples of silver salts include silver nitrate, silver sulfate, silver chloride, silver bromide, silver oxide, silver acetate, silver carbonate, silver citrate, silver lactate, silver phosphate, silver oxalate, silver thiosulfate, and silver protein, with silver nitrate being preferred.

[0116] In the present invention, the concentration of the silver salt is not particularly limited, and is not particularly limited as long as it is within the range of, for example, 0.00000001 to 1% (w / v). Specifically, the lower limit value is, for example, 0.00000001% (w / v) or more, 0.0000001% (w / v) or more, 0.000001% (w / v) or more, 0.0000025% (w / v) or more, 0.000004% (w / v) or more, 0.000005% (w / v) or more, 0.000008% (w / v) or more, 0.00001% (w / v) or more, 0.000016% (w / v) or more, 0.000025% (w / v) or more, 0.00004% (w / v) or more, 0. Preferably, the concentration is 00005% (w / v) or more, 0.00008% (w / v) or more, or 0.0001% (w / v) or more. The upper limit is preferably, for example, 1% (w / v) or less, 0.5% (w / v) or less, 0.1% (w / v) or less, 0.05% (w / v) or less, 0.01% (w / v) or less, 0.005% (w / v) or less, or 0.001% (w / v) or less.

[0117] In addition to the polyvinylpyrrolidone and preservatives, pharma- ceutically acceptable additives may be added to the composition as necessary. For example, buffers such as sodium phosphate, sodium hydrogen phosphate, sodium hydrogen phosphate hydrate, sodium dihydrogen phosphate, sodium acetate, and epsilon-aminocaproic acid; isotonicity agents such as calcium chloride, sodium chloride, potassium chloride, and concentrated glycerin; stabilizers such as sodium edetate, sodium edetate hydrate, citric acid hydrate, and sodium citrate hydrate; surfactants such as polysorbates; antioxidants such as ascorbic acid; thickeners (also called thickeners) such as hydroxyethylcellulose and hydroxypropylmethylcellulose; and pH regulators such as hydrochloric acid and sodium hydroxide may be selected and added as necessary. These additives may be used alone or in any combination of two or more. The composition may not contain a cellulose polymer, which is a thickener, such as hydroxyethylcellulose and hydroxypropylmethylcellulose.

[0118] The pH of the composition is not limited to a specific value as long as it is within a medicament-acceptable range. However, the pH of the composition is preferably 8 or less, more preferably 4 to 8, even more preferably 5 to 8, even more preferably 6 to 8, especially preferably 7 to 8, and particularly preferably around 7. More specifically, for example, pH 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0 are preferred, and 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0 are more preferred.

[0119] In the present invention, the term "ophthalmic composition" refers to a composition used for the prevention and / or treatment of eye diseases, etc. The dosage form thereof may be, for example, eye drops, eye ointments, injections, ointments (for example, that can be administered to the eyelid skin), etc., and eye drops are preferred. Here, eye drops are synonymous with eye drops or eye drops, and eye drops for contact lenses are also included in the definition of eye drops.

[0120] In the present invention, the "aqueous ophthalmic composition" is an aqueous ophthalmic composition containing water as a solvent (base), and is more preferably an aqueous eye drop.

[0121] The present composition may be in the form of a solution-type eye drop or a suspension-type eye drop depending on the properties and contents of the active ingredient and additives.

[0122] The composition is preferably a sterile aqueous ophthalmic solution. Here, "sterile" refers to a state in which microorganisms have been killed or removed, specifically, for example, a state that meets the preservative effectiveness test standards described in the Japanese Pharmacopoeia, 17th Edition.

[0123] The composition is preferably storable at room temperature.

[0124] The viscosity of the composition is not particularly limited as long as it is within a medicamentously acceptable range, but for example, it is preferably within the range of 1 to 500 mPa·s, more preferably within the range of more than 1.4 to 100 mPa·s, even more preferably within the range of 1.5 to 100 mPa·s, still more preferably within the range of 1.5 to 50 mPa·s, and even more preferably within the range of 1.5 to 30 mPa·s. The viscosity of the composition is adjusted to be within the range of 1.5 to 30 mPa·s, preferably within the range of 2 to 30 mPa·s, more preferably within the range of 3 to 30 mPa·s, more preferably within the range of 5 to 10 mPa·s, and even more preferably within the range of 7 to 10 mPa·s. The viscosity of the composition can also be adjusted to be within the range of 1.5 to 30 mPa·s, preferably within the range of 2 to 30 mPa·s, more preferably within the range of 3 to 30 mPa·s, even more preferably within the range of 5 to 30 mPa·s, and even more preferably within the range of 7 to 30 mPa·s. The lower limit of the viscosity of the composition is preferably 1 mPa·s or more, 1.5 mPa·s or more, 2 mPa·s or more, 3 mPa·s or more, 5 mPa·s or more, or 7 mPa·s or more. The upper limit is preferably, for example, 500 mPa·s or less, 100 mPa·s or less, 50 mPa·s or less, 30 mPa·s or less, 20 mPa·s or less, or 10 mPa·s or less. -1 The shear rate is measured at 100 MPa.

[0125] The osmotic pressure of the composition is not limited to a specific value as long as it is within a medicament-acceptable range, but is preferably 2 or less, more preferably in the range of 0.5 to 2, even more preferably in the range of 0.7 to 1.6, even more preferably in the range of 0.8 to 1.4, and particularly preferably in the range of 0.9 to 1.2.

[0126] The present composition can be stored in an airtight container, specifically, an eye drop container. Examples of the eye drop container in which the present composition is filled include a "multi-dose eye drop container" or a "unit dose eye drop container."

[0127] In the present invention, the term "ophthalmic medicinal product" refers to an ophthalmic medicinal product in which the present composition is filled in an eye drop container. Here, the "ophthalmic medicinal product" may be, for example, an eye drop product. The definitions of each term in the "ophthalmic medicinal product" of the present invention are the same as those in the "composition".

[0128] In the present invention, the term "multi-dose eye drop container" refers to an eye drop container having a container body and a cap that can be attached to the container body, and the cap can be freely opened and resealed. The multi-dose eye drop container usually contains multiple doses of eye drops for use over a certain period of time. In addition, when the composition does not contain a preservative such as benzalkonium chloride, the composition may be contained in a PFMD (Preservative Free Multi Dose) container. The amount of the composition filled in the multi-dose eye drop container or PFMD container is, for example, preferably 1 to 20 mL, more preferably 1 to 15 mL, even more preferably 1 to 10 mL, even more preferably 2.5 to 10 mL, and particularly preferably 5 mL.

[0129] On the other hand, the term "unit dose eye drop container" refers to an eye drop container in which a cap is fused and sealed to the mouth of the bottle, and the fused part between the cap and the bottle-shaped body is broken and opened when used. The unit dose eye drop container contains an amount of eye drop solution for one or several uses. The eye drop solution contained in the unit dose eye drop container generally does not contain a preservative such as benzalkonium chloride. The amount of the composition filled in the unit dose eye drop container is, for example, preferably 0.1 to 1 mL, more preferably 0.1 to 0.5 mL, even more preferably 0.3 mL to 0.5 mL, and particularly preferably 0.3 mL or 0.4 mL.

[0130] The method of administration of the present composition can be appropriately changed depending on the dosage form, the severity of the symptoms of the patient to be administered, the age, weight, the doctor's judgment, etc. For example, when eye drops are selected as the dosage form, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop is administered at a time. The eye drops can be administered 1 to 6 times a day, preferably 1 to 4 times a day, more preferably 2 to 4 times a day, and even more preferably 3 times a day, every day to every week. More specifically, the frequency of administration is preferably 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day, or once a day, more preferably 6 times a day, 4 times a day, 3 times a day, or twice a day, further preferably 4 times a day, 3 times a day, or twice a day, and particularly preferably 3 times a day.

[0131] Furthermore, when the concentration of diquafosol or a salt thereof in the composition is 3% (w / v), 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, and particularly preferably 1 drop can be administered by instillation into the eyes 6 times a day, 5 times a day, 4 times a day, 3 times a day, 2 times a day or once a day, preferably 6 times a day, 4 times a day, 3 times a day or 2 times a day, more preferably 4 times a day or 3 times a day, and particularly preferably 3 times a day.

[0132] Moreover, one drop is preferably 10 to 50 μL, more preferably 20 to 50 μL, and particularly preferably 40 to 50 μL.

[0133] This composition is used for the prevention or treatment of dry eye, and is effective as a preventive or therapeutic agent for dry eye. Dry eye is defined as "a chronic disease of the tear fluid and corneal and conjunctival epithelium caused by various factors, which is accompanied by ocular discomfort and visual abnormalities," and keratoconjunctivitis sicca (KCS) is included in dry eye. In the present invention, the occurrence of dry eye symptoms caused by wearing soft contact lenses is also included in dry eye.

[0134] Dry eye symptoms include subjective symptoms such as dry eye, eye discomfort, eye fatigue, dullness, photophobia, eye pain, blurred vision, etc., as well as objective findings such as congestion, corneal and conjunctival epithelial disorders, etc. In the present invention, "prevention or treatment of dry eye" also includes improvement of the subjective symptoms and / or objective findings.

[0135] There are many unknowns about the etiology of dry eye, but reported causes include Sjogren's syndrome; congenital alacrimal gland deficiency; sarcoidosis; graft versus host disease (GVHD) due to bone marrow transplantation; ocular pemphigoid; Stevens-Johnson syndrome; lacrimal obstruction due to trachoma; diabetes; decreased reflex secretion due to corneal refractive surgery (LASIK: Laser(-assisted) in situ keratomileusis); meibomian gland dysfunction; decreased oil layer due to blepharitis; insufficient blinking or eyelid closure due to exophthalmos or lagophthalmos; decreased mucin secretion from germ cells; and working with VDTs (Visual Display Terminals).

[0136] The composition can also be instilled into the eyes of a dry eye patient wearing a soft contact lens. Here, instillation into the eyes of a dry eye patient wearing a soft contact lens means that the eye drops are instilled into the eyes of the dry eye patient while the soft contact lens is being worn on the cornea of ​​the dry eye patient. EXAMPLES

[0137] The results of pharmacological tests and formulation examples are shown below for a better understanding of the present invention, but they are not intended to limit the scope of the present invention.

[0138] [Test 1] Using normal male white rabbits, the change in tear volume over time after instillation of the composition was evaluated.

[0139] (Sample preparation method) Eye drops 1: According to the prescription shown in Table 1, eye drop solution 1 was prepared. That is, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL, and a 6-fold concentrated solution was obtained. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH regulator was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. PVP K90 (4 g) was dissolved in sterile purified water to make the total amount 100 g, and then the solution was sterilized by high-pressure steam (121°C for 20 minutes) to obtain a 4.00% (w / w) PVP K90 solution. Ophthalmic solution 1 was prepared by adding 4 mL of the 3x concentrated solution to 6.0 g of 4.00% (w / w) PVP K90 solution, adjusting the total volume to 12 mL with sterile purified water, and then adjusting the pH to 7 by adding an appropriate pH adjuster.

[0140] Eye drops 2: According to the prescription shown in Table 1, eye drop solution 2 was prepared. That is, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL, to obtain a 6-fold concentrated solution. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and PVP K30 (1.2 g) was dissolved therein, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Sterile purified water was added to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then a pH adjuster was appropriately added to adjust the pH to 7, to prepare eye drop solution 2.

[0141] Eye drops 3: According to the prescription shown in Table 1, eye drop solution 3 was prepared. That is, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g) and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL, and a 6-fold concentrated solution was obtained. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH regulator was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Hydroxyethylcellulose (15 g) was dissolved in 1500 mL of sterile purified water, and the solution was sterilized by high-pressure steam (121°C for 20 minutes) to obtain a 1.00% (w / w) hydroxyethylcellulose solution. 4 mL of the 3-fold concentrated solution was added to 3.6 g of 1.00% (w / w) hydroxyethylcellulose solution, and the total volume was adjusted to 12 mL by adding sterile purified water, and then a pH regulator was appropriately added to adjust the pH to 7, to prepare eye drop solution 3.

[0142] Eye drops 4: Ophthalmic solution 4 was prepared according to the prescription shown in Table 1. That is, diquafosol sodium (9 g), sodium hydrogen phosphate hydrate (0.6 g), sodium edetate hydrate (0.03 g), and sodium chloride (1.35 g) were dissolved in sterile purified water to make 50 mL, to obtain a 6-fold concentrated solution. In addition, 10 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then a pH adjuster was appropriately added to adjust the pH to 7, and sterile purified water was added to make 20 mL, to obtain a 3-fold concentrated solution. Sterile purified water was added to 4 mL of the 3-fold concentrated solution to make a total volume of 12 mL, and then a pH adjuster was appropriately added to adjust the pH to 7, to prepare ophthalmic solution 4.

[0143] Eye drops 5: Ophthalmic solution 5 was prepared according to the prescription shown in Table 1. That is, diquafosol sodium (18 g), sodium hydrogen phosphate hydrate (1.2 g), and sodium edetate hydrate (0.06 g) were dissolved in sterile purified water to make 100 mL, to obtain a 6-fold concentrated solution. In addition, 2.5 mL of the 6-fold concentrated solution was mixed with 5 mL of sterile purified water, and then 45% aqueous solution of PVP K60 (0.67 g) and sodium chloride (0.068 g) were dissolved therein, and the pH was adjusted to 7 by adding an appropriate pH adjuster. Then, sterile purified water was added to make up to 15 mL to prepare eye drop solution 5.

[0144] The viscosity of the prepared eye drops 1 to 5 was measured according to the method described in the 17th revised Japanese Pharmacopoeia, 2.53 Viscosity measurement method, Method 2 Rotational viscometer method, and 2.1.3 Cone-plate type rotational viscometer (cone-plate type viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows. (Measurement conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

[0145] (Testing Method and Drug Administration Method) Benoxil was administered to normal male white rabbits (total of 16 rabbits, 32 eyes). (登録商標) A 0.4% eye drop (Santen Pharmaceutical Co., Ltd.) was instilled into the eye and local anesthesia was administered. After 3 minutes, Schirmer test paper (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed and the length of the wetted area (tear volume) was read. This was used as the baseline value. Next, eye drops 1 to 5 were instilled once (8 eyes of 4 animals in each group, eye drop 4 only was administered to 24 eyes of 12 animals). 3 minutes before inserting the Schirmer test paper (Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil (登録商標) Local anesthesia was administered by instilling 0.4% eye drops (Santen Pharmaceutical Co., Ltd.). Sixty minutes after instillation of each eye drop, a Schirmer test strip (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid and removed one minute later to measure the length of the wetted area (tear volume).

[0146] (Evaluation method) The change in tear volume before and after instillation of the eye drops was calculated as Δtear volume (mm / min).

[0147] (Test Results) The Δ tear volume (mm / min) 60 minutes after instillation is shown in Tables 1 and 2 (each value is the average of 8 eyes, except for eye drop 4, which is the average of 24 eyes). The tear volume increasing effect of the composition was evaluated according to the following criteria. +++: Delta tear volume (mm / min) 4mm / min or more 60 minutes after instillation ++: Δ tear volume (mm / min) 60 minutes after instillation is 1mm / min or more and less than 4mm / min +: Δ tear volume (mm / min) 60 minutes after instillation is greater than 0mm / min or less than 1mm / min -: Delta tear volume (mm / min) 0mm / min or less 60 minutes after instillation

[0148] [Table 1]

[0149] As shown in the results in Table 1 above, the eye drops containing PVP K30 (eye drops 2) did not show any tear volume increase 60 minutes after administration, similar to the eye drops not containing PVP K30 (eye drops 4). Furthermore, although HEC is generally used as a thickening agent, the eye drops containing HEC (eye drops 3) did not show any tear volume increase 60 minutes after administration, similar to eye drops 4, despite having a relatively high viscosity. In contrast, the eye drops containing PVP K90 (eye drops 1) showed a significantly higher tear volume increase effect than eye drops 2 to 4.

[0150] [Table 2]

[0151] As shown in the results in Table 2 above, even though the K value of PVP was 60, the eye drops containing PVP (eye drops 5) had a high tear volume increasing effect.

[0152] (Consideration) Polyvinylpyrrolidone increased the viscosity of the aqueous composition containing diquafosol or a salt thereof, and enhanced the medicinal efficacy of diquafosol or a salt thereof. In particular, it was shown that the medicinal efficacy of diquafosol or a salt thereof was significantly enhanced when polyvinylpyrrolidone having a K value of more than 30 was added or when the viscosity of the aqueous composition exceeded 1.4 due to the addition of polyvinylpyrrolidone.

[0153] [Test 2] The rat extraorbital lacrimal gland removal model is widely used as a model for evaluating the therapeutic effect of corneal epithelial damage caused by dry eye, and is also used as a model for evaluating the therapeutic effect of P2Y2 receptor agonists (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). Using this dry eye model, we investigated whether the present composition can be administered by eye drop to improve corneal epithelial damage.

[0154] (Method of preparing a dry eye model) A rat extraorbital lacrimal gland removal model was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci., 42(1), 96-100 (2001)). After administering Somnopentyl to give general anesthesia, the extraorbital lacrimal gland was removed to induce corneal epithelial damage.

[0155] (Sample preparation method) Eye Drop A: Sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and diquafosol sodium (3 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0156] Eye Drops B: Sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and polyvinylpyrrolidone K90 (4 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0157] Eye Drops X: Eye drops X, which is used as a treatment for dry eyes, (登録商標) "Ophthalmic Solution 3%" (Santen Pharmaceutical Co., Ltd.) was used. Ophthalmic Solution X contains 30 mg of diquafosol sodium as the active ingredient in 1 mL of water, and also contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate hydrate, and a pH adjuster as additives.

[0158] The viscosities of the prepared eye drops A, B and X were measured according to the method described in the 17th Revised Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2 Rotational Viscometer Method, and 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows: (Measurement conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

[0159] The measured viscosities of each eye drop were as follows: Eye drop A: 7.9 mPa·s Eye drop B: 28.0 mPa s Eye drops X: 0.9 mPa·s (Testing Method and Drug Administration Method) To the rats with corneal epithelial damage induced as described above, eye drops A, B, and X were administered as follows. Group administered eye drops A three times a day: Eye drops A was administered to both eyes three times a day for four weeks (12 eyes in 6 animals per group). Group administered eye drops B, 3 times a day: Eye drops B was administered to both eyes 3 times a day for 4 weeks (12 eyes in 6 animals per group). Eye drops X, 6 times a day group: Eye drops X was administered to both eyes 6 times a day for 4 weeks (12 eyes, 6 animals per group). Rats without corneal epithelial damage and without administration of any eye drops for 4 weeks were classified as the no-drop group (4 rats, 8 eyes per group).

[0160] Four weeks after the start of eye drops, the damaged areas of the cornea were stained with fluorescein, and corneal epithelial damage was evaluated according to the method of Murakami et al. (New Eyes, 21(1), 87-90 (2004)). That is, the degree of fluorescein staining of the upper, middle, and lower parts of the cornea was scored according to the following criteria, and the average of the total scores was calculated. A midpoint of 0.5 was set between scores of 0, 1, 2, and 3.

[0161] (Judgment criteria) 0: not stained, 1: Staining is sparse, with each spot of staining separated; 2: Staining is moderate, with some dot-like staining areas adjacent to each other. 3: Dense staining, with each spot of staining adjacent to each other.

[0162] (result) The calculated fluorescein staining scores for each group are shown in a graph in Figure 1. The scores are the mean value + standard error of 8 or 12 cases.

[0163] As is clear from Figure 1, in the group administered ophthalmic solution A three times a day, improvement in fluorescein staining score was observed from two weeks after the start of administration compared to the group administered ophthalmic solution B three times a day. In the group administered ophthalmic solution X six times a day, improvement in fluorescein staining score was observed from four weeks after the start of administration compared to the group administered ophthalmic solution B three times a day. Four weeks after administration, the group administered ophthalmic solution A three times a day and the group administered ophthalmic solution X six times a day showed similar effects.

[0164] (Consideration) Eye drops X is "Diquas (登録商標) It is used to treat dry eye as "Diquas ophthalmic solution 3%" and is instilled six times a day. It has been revealed that this composition containing polyvinylpyrrolidone K90 has a sufficient therapeutic effect on dry eye when instilled three times a day, and especially after two weeks of instillation, (登録商標) The therapeutic effect of this composition was found to be superior to that of the existing Diquas ophthalmic solution, which was administered six times a day. (登録商標) It can be instilled less frequently than conventional eye drops. (登録商標) In particular, taking into account the results of Test 1, the present composition containing polyvinylpyrrolidone with a K value of more than 30 or the present composition with a viscosity of more than 1.4 due to the addition of polyvinylpyrrolidone, when instilled 2 to 4 times a day, is more effective than the existing "Diquas Eye Drops" (登録商標) It was suggested that this treatment had a therapeutic effect equivalent to or greater than that of instilling 3% eye drops six times a day.

[0165] [Test 3] In order to examine the effect of this composition on corneal epithelial cells, a test on cytotoxicity to corneal epithelial cells was carried out.

[0166] (Sample preparation method) According to the formulations shown in Table 3, eye drops Y, C and D were prepared.

[0167] Eye Drops Y: Eye drops Y were prepared according to the formulation shown in Table 3. Specifically, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), and diquafosol sodium (3 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0168] Eye drops C and D: According to the formulations shown in Table 3, eye drops C and D were prepared in the same manner as eye drops Y.

[0169] The viscosities of the prepared eye drops Y, C and D were measured according to the method described in the 17th Revised Japanese Pharmacopoeia, 2.53 Viscosity Measurement Method, Method 2 Rotational Viscometer Method, and 2.1.3 Cone-Plate Rotational Viscometer (Cone-Plate Viscometer). Specifically, Kinexus pro+ (manufactured by Malvern) was used, and the measurement conditions were set as follows: (Measurement conditions) Rotor angle: 1° Rotor diameter: 50mm Sample volume: 0.57mL Measurement temperature: 25℃ Shear rate: 50s -1 Measurement time: The viscosity was measured every 2 seconds, and the average value for 1 minute was recorded as the viscosity.

[0170] [Table 3]

[0171] (Test Method) SV40-immortalized human corneal epithelial cells (HCE-T: RIKEN BioResource Center, Cell No.: RCB2280) were seeded in a 96-well plate (1 × 10 4 The cells were then cultured in D-MEM / F12 medium containing 10% FBS for one day. On the following day, the medium was replaced with eye drop solution Y, C, or D, and the corneal epithelial cells were cultured for 5, 10, or 15 minutes. Viable cell activity (corresponding to absorbance at 490 nm) was measured using a Cell Proliferation Assay Kit (Promega, catalog number: G3580).

[0172] (result) The test results are shown in Figure 2.

[0173] As is clear from Figure 2, Diquafosol ophthalmic solution containing polyvinylpyrrolidone (ophthalmic solutions C and D) maintained a high viability of immortalized human corneal epithelial cells even after 15 minutes of culture. On the other hand, Diquafosol ophthalmic solution not containing polyvinylpyrrolidone (ophthalmic solution Y) showed a decrease in viability over time.

[0174] (Consideration) Diquafosol ophthalmic solution containing polyvinylpyrrolidone exhibits high viability in cultured immortalized human corneal epithelial cells and is therefore safer for the corneal and conjunctival epithelium and is useful for treating diseases in which the corneal and conjunctival epithelium is unstable, such as dry eye.

[0175] [Test 4] The irritation of peripheral nerves by diquafosol sodium in the presence of PVP was investigated.

[0176] (Sample preparation method) Formulation 1: According to the recipe shown in Table 4, formulation solution 1 was prepared. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, and a pH adjuster was added to adjust the pH to 7.5, and the total volume was adjusted to 100 mL to obtain a 10x buffer solution. PVP K30 (16 g) was dissolved in sterile purified water, and the total volume was adjusted to 200 mL to obtain an 8% PVP K30 aqueous solution. 2 mL of the 10x buffer solution and 5 mL of the 8% PVP K30 aqueous solution were weighed out, and the total volume was adjusted to 20 mL with sterile purified water, and the pH was adjusted to 7.5 using a pH adjuster to obtain formulation solution 1.

[0177] Formulation 2: Formulation solution 2 was prepared according to the recipe shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10x buffer solution. 2 mL of the 10x buffer solution and PVP K90 (0.4 g) were dissolved in sterile purified water, the pH was adjusted to 7.5 using a pH adjuster, and the total volume was adjusted to 20 mL to obtain formulation solution 2.

[0178] Formulation 3: Formulation solution 3 was prepared according to the recipe shown in Table 4. That is, sodium chloride (8.5 g) and sodium hydrogen phosphate hydrate (2 g) were dissolved in sterile purified water, a pH adjuster was added, the pH was adjusted to 7.5, and the total volume was adjusted to 100 mL to obtain a 10x buffer solution. 2 mL of the 10x buffer solution and sodium chondroitin sulfate (0.06 g) were added to sterile purified water, the pH was adjusted to 7.5 using the pH adjuster, dissolution was confirmed, and the total volume was adjusted to 20 mL to obtain formulation solution 3.

[0179] Formulations 4-6: According to the formulation shown in Table 4, formulations 4 to 6 were prepared in the same manner as formulation 3.

[0180] [Table 4]

[0181] (Test Method) Cultured peripheral nerve cells (rat dorsal root ganglion neurons, purchased from Lonza Japan) were incubated in a buffer solution containing an intracellular calcium indicator fluorescent dye (FLIPR Calcium 6 Assay Kit, Molecular Devices). 40% of the total volume of the buffer solution was replaced with each of the above-mentioned formulation solutions. The non-stimulated group and stimulated control group were treated in the same manner with buffer solution instead of the formulation solution. After leaving the cells to stand at room temperature, time-dependent fluorescence measurement of the calcium indicator dye was started using a fluorescent plate reader. Diquafosol sodium (final concentration: 0.3%) was added 60 seconds after the start, and the measurement of fluorescence intensity was continued.

[0182] (Evaluation method) The fluorescence intensity (RFU) immediately before the addition of diquafosol sodium was defined as 100%, and the maximum fluorescence intensity (RFUmax) after the addition was calculated.

[0183] (Test Results) The results are shown in Figure 3. In the stimulation control group and formulations 3 to 6, the RFU increased after the addition of diquafosol sodium, recording an RFUmax of 103.5% or more. On the other hand, in the groups of formulations 1 and 2 containing PVP, the RFUmax was all less than 101%.

[0184] (Consideration) Peripheral nerve cells that receive some kind of stimulus generate an action potential and become excited, and the stimulus signal converted into the action potential is then transmitted to the central nervous system. An action potential is a change in cell membrane potential caused by the influx of cations, including calcium ions, into the cells. Therefore, an increase in intracellular calcium ion concentration is widely used experimentally as an index of the excited state of nerve cells. When peripheral nerve cells were exposed to diquafosol sodium, an increase in the fluorescence intensity of intracellular calcium ions was observed immediately, indicating that the nerve cells received diquafosol sodium as a stimulus and became excited. A similar stimulus response was observed in each of the groups of polymer formulations 3 to 6 that did not contain PVP, which were used as comparative examples, and the polymers sodium chondroitin sulfate, HPMC, CVP, and CMC-Na did not have any effect on the nerve irritation of diquafosol sodium. In contrast, in formulations 1 and 2 that contained PVP, no increase in intracellular calcium ion signals was observed after the addition of diquafosol sodium. In other words, it was suggested that diquafosol sodium in the presence of PVP did not exhibit neuroirritation, and the addition of PVP improved the sensation of application of diquafosol sodium ophthalmic solution.

[0185] [Test 5] The effect of this composition on the stability of preservatives was examined.

[0186] (Sample preparation method) Eye drops 6: Ophthalmic solution 6 was prepared according to the formulation shown in Table 5. Specifically, diquafosol sodium (3 g), chlorhexidine gluconate (0.0025 g), hydroxyethylcellulose (0.2 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), and sodium chloride (0.45 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0187] Eye drops 7-10: According to the formulations shown in Table 5, eye drops 7 to 10 were prepared in the same manner as eye drops 6.

[0188] [Table 5]

[0189] (Test Method) The chlorhexidine gluconate content of eye drops 6 and 7 was quantified using high performance liquid chromatography (HPLC) when each was stored at 60°C for up to 4 weeks, and the remaining rate (%) was calculated. The chlorhexidine gluconate content of eye drops 8 and 9 was quantified using high performance liquid chromatography (HPLC) when each was stored at 60°C for up to 2 weeks, and the remaining rate (%) was calculated. The silver nitrate content of eye drops 10 was quantified using inductively coupled plasma atomic emission spectrometry (ICP-AES) when each was stored at 60°C for up to 4 weeks, and the remaining rate (%) was calculated.

[0190] (Test Results) The results of the stability test are shown in Table 6.

[0191] [Table 6]

[0192] (Consideration) In an aqueous ophthalmic composition (the present composition) containing diquafosol or a salt thereof and polyvinylpyrrolidone, when chlorhexidine gluconate was contained as a preservative, the residual rate was significantly decreased (ophthalmic solutions 7 to 9). On the other hand, when silver nitrate, a silver salt, was contained as a preservative, the residual rate was high (ophthalmic solution 10). From the above, it was demonstrated that the present composition destabilizes chlorhexidine gluconate while stabilizing silver salts.

[0193] [Test 6] The preservative effectiveness of this composition containing a silver salt was investigated.

[0194] (Sample preparation method) Eye drops 11: Ophthalmic solution 11 was prepared according to the formulation shown in Table 7. Specifically, diquafosol sodium (3 g), silver nitrate (0.00008 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K30 (2 g), concentrated glycerin (1.2 g), and hydroxyethyl cellulose (0.25 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0195] Eye drops 12-15: According to the formulation shown in Table 7, eye drops 12 to 15 were prepared in the same manner as eye drops 11.

[0196] [Table 7]

[0197] (Test Method) The preservative effectiveness test was performed in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. The test bacteria used in this test were Escherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis).

[0198] (Test Results) The test results are shown in Table 8.

[0199] [Table 8]

[0200] The test results in Table 8 are shown in log reduction, which indicates the degree to which the number of live bacteria at the time of testing was reduced compared to the number of bacteria inoculated. For example, a value of "1" indicates that the number of live bacteria at the time of testing was reduced to 10% of the number of bacteria inoculated.

[0201] As shown in Table 8, the composition containing a silver salt was shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia.

[0202] (Consideration) The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[0203] [Test 7] Using normal male white rabbits, the change in tear volume over time 90 minutes after instillation of the composition was evaluated.

[0204] (Sample preparation method) Eye Drops 16: To prepare eye drops 16, sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), sodium chloride (0.45 g), silver nitrate (0.00004 g), polyvinylpyrrolidone K90 (2 g), and diquafosol sodium (3 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0205] Eye Drops 17: Diquas is used as an eye drop17 for the treatment of dry eye. (登録商標) Eye Drops 17 (3% Ophthalmic Solution, manufactured by Santen Pharmaceutical Co., Ltd.) was used. Eye Drops 17 contains 30 mg of diquafosol sodium as an active ingredient in 1 mL of water, and contains potassium chloride, sodium chloride, chlorhexidine gluconate solution, sodium hydrogen phosphate hydrate, sodium edetate, and 100 mg of ethylhexyl 2-methyl-2-propanol as additives. Contains sodium hydrate and pH adjuster.

[0206] (Testing Method and Drug Administration Method) Benoxil was administered to normal male white rabbits (total of 12 rabbits, 24 eyes). (登録商標) A 0.4% eye drop (Santen Pharmaceutical Co., Ltd.) was instilled into the eye to administer local anesthesia. After 3 minutes, a Schirmer test strip (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid, and 1 minute after insertion, it was removed and the length of the wetted area (tear volume) was read. This was used as the baseline value. Next, eye drops 16 and 17 were instilled once (12 eyes of 6 animals per group). 3 minutes before inserting the Schirmer test strip (Ayumi Pharmaceutical Co., Ltd.) into the lower eyelid, Benoxil (登録商標) Local anesthesia was administered by instilling 0.4% eye drops (Santen Pharmaceutical Co., Ltd.). 90 minutes after instillation of each eye drop, a Schirmer test strip (Ayumi Pharmaceutical Co., Ltd.) was inserted into the lower eyelid and removed 1 minute later to measure the length of the wetted area (tear volume).

[0207] (Evaluation method) The change in tear volume before and after instillation of the eye drops was calculated as Δtear volume (mm / min).

[0208] (Test Results) The Δ tear volume (mm / min) 90 minutes after instillation is shown in Table 9 (each value is the average value of 12 eyes). The tear volume increasing effect of the composition was evaluated according to the following criteria. +++: Delta tear volume (mm / min) 4mm / min or more 90 minutes after instillation ++: Δ tear volume (mm / min) 90 minutes after instillation is 1mm / min or more and less than 4mm / min +: Δ tear volume (mm / min) 90 minutes after instillation is greater than 0mm / min or less than 1mm / min -: Delta tear volume (mm / min) 0mm / min or less 90 minutes after instillation

[0209] [Table 9]

[0210] As shown by the results in Table 9 above, the composition exhibited a high tear volume increasing effect even 90 minutes after instillation.

[0211] [Test 8] The preservative effectiveness of this composition containing a silver salt was investigated.

[0212] (Sample preparation method) Eye drops 18: Ophthalmic solution 18 was prepared according to the formulation shown in Table 10. Specifically, diquafosol sodium (3 g), silver nitrate (0.00003 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.0.

[0213] Eye Drops 19: According to the formulation shown in Table 10, eye drop solution 19 was prepared in the same manner as eye drop solution 18.

[0214] [Table 10]

[0215] (Test Method) The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. In this test, the test bacteria used were Escherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis).

[0216] (Test Results) The test results are shown in Table 11.

[0217] [Table 11]

[0218] The test results in Table 11 show the log reduction of the number of live bacteria at the time of testing compared to the number of bacteria inoculated. For example, "1" indicates the degree to which the number of live bacteria at the time of testing was reduced compared to the number of bacteria inoculated. This shows that the number of bacteria was reduced to 10% of the inoculum.

[0219] As shown in Table 11, the present compositions containing silver salts, with or without EDTA, were shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia.

[0220] (Consideration) The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[0221] [Test 9] The preservative effectiveness of this composition containing a silver salt was investigated.

[0222] (Sample preparation method) Eye Drops 20: Ophthalmic solution 20 was prepared according to the formulation shown in Table 12. Specifically, diquafosol sodium (3 g), silver nitrate (0.00004 g), sodium hydrogen phosphate hydrate (0.2 g), sodium edetate hydrate (0.01 g), polyvinylpyrrolidone K90 (2 g), and sodium chloride (0.45 g) were dissolved in sterile purified water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5.

[0223] Eye drops 21-23: According to the formulation shown in Table 12, eye drops 21 to 23 were prepared in the same manner as eye drops 20.

[0224] [Table 12]

[0225] (Test Method) The preservative effectiveness test was conducted in accordance with the preservative effectiveness test method of the 17th edition of the Japanese Pharmacopoeia. In this test, the test bacteria used were Escherichia Coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), Candida albicans (C. albicans), and Aspergillus brasiliensis (A. brasiliensis).

[0226] (Test Results) The test results are shown in Table 13.

[0227] [Table 13]

[0228] The test results in Table 13 are shown in log reduction, which indicates the degree to which the number of live bacteria at the time of testing was reduced compared to the number of bacteria inoculated. For example, a value of "1" indicates that the number of live bacteria at the time of testing was reduced to 10% of the number of bacteria inoculated.

[0229] As shown in Table 13, the composition containing a silver salt, with or without EDTA, was shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia. In addition, eye drops containing silver phosphate and silver chloride, in addition to silver nitrate, were also shown to meet the preservative effectiveness test standards of the Japanese Pharmacopoeia.

[0230] (Consideration) The above results demonstrate that the composition containing a silver salt has excellent preservative effectiveness.

[0231] [Test 10] The effect of this composition on the stability of preservatives was examined.

[0232] (Sample preparation method) Eye Drops 24: Diquafosol sodium (3 g), sodium edetate hydrate (0.01 g), sodium hydrogen phosphate hydrate (0.2 g), sodium chloride (0.45 g), polyvinylpyrrolidone K90 (2 g), and silver nitrate (0.00004 g) were dissolved in water to make 100 mL, and a pH adjuster (qs) was added to adjust the pH to 7.5 to prepare ophthalmic solution 24.

[0233] (Test Method) The silver nitrate content in the eye drops 24 was quantified using inductively coupled plasma atomic emission spectrometry (ICP-AES) after storage at 40°C for up to 6 months, and the residual rate (%) was calculated.

[0234] (Test Results) The results of the stability study are shown in Table 14.

[0235] [Table 14]

[0236] (Consideration) When silver nitrate, a silver salt, was added as a preservative, the retention rate was high. From the above, it was demonstrated that the silver salt is stable in this composition.

[0237] [Formulation example] The pharmaceutical agent of the present invention will be explained in more detail with reference to formulation examples, but the present invention is not limited to these formulation examples.

[0238] (Formulation Example 1: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. Also, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

[0239] (Formulation Example 2: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. Also, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

[0240] (Formulation Example 3: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K40 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. An ophthalmic medicinal product can be manufactured by filling 1 to 10 mL of the above eye drop solution into a multi-dose eye drop container or a PFMD container. In addition, an ophthalmic pharmaceutical product can be manufactured by filling 0.1 to 1 mL of the above eye drop solution into a unit-dose eye drop container. The above eye drop solution can be stored at room temperature.

[0241] (Formulation Example 4: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop preparation can be stored at room temperature.

[0242] (Formulation Example 5: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop solution can be stored at room temperature.

[0243] (Formulation Example 6: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Sodium edetate hydrate 0.0001~0.1g Polyvinylpyrrolidone K40 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop preparation can be stored at room temperature.

[0244] (Formulation Example 7: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drops can be prepared by adding diquafosol sodium and the other above ingredients to the sterile purified solution and thoroughly mixing them. 1 to 10 mL of the above eye drops can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. Also, 0.1 to 1 mL of the above eye drops can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drops can be stored at room temperature.

[0245] (Formulation Example 8: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K60 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. In addition, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop preparation can be stored at room temperature.

[0246] (Formulation Example 9: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K40 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. In addition, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop preparation can be stored at room temperature.

[0247] (Formulation Example 10: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. The eye drops can be stored at room temperature.

[0248] (Formulation Example 11: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K60 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop preparation can be stored at room temperature.

[0249] (Formulation Example 12: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Polyvinylpyrrolidone K40 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop preparation can be stored at room temperature.

[0250] (Formulation Example 13: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Citric acid hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container or a PFMD container to produce an ophthalmic medicinal product. In addition, 0.1 to 1 mL of the above eye drop solution can be filled into a unit-dose eye drop container to produce an ophthalmic medicinal product. The above eye drop preparation can be stored at room temperature.

[0251] (Formulation Example 14: Sterile aqueous ophthalmic solution (3% (w / v)) in 100mL Diquafosol sodium 3g Sodium hydrogen phosphate hydrate 0.01~0.5g Sodium chloride 0.01~1g Citric acid hydrate 0.0001~0.1g Polyvinylpyrrolidone K90 0.0001~10g Silver nitrate 0.00000001~1g pH adjuster (appropriate amount) The above eye drop solution can be prepared by adding diquafosol sodium and the other above ingredients to sterile purified water and thoroughly mixing them. 1 to 10 mL of the above eye drop solution can be filled into a multi-dose eye drop container to produce an ophthalmic pharmaceutical product. The above eye drop preparation can be stored at room temperature. [Industrial Applicability]

[0252] Existing Ziquas (登録商標) The eye drops need to be instilled six times a day, but there are some severe dry eye patients who do not achieve sufficient therapeutic effects even when using the prescribed dosage. Furthermore, there are also patients who do not achieve the expected effect due to poor adherence to the eye drops. (登録商標) This composition is expected to have a stronger effect on treating dry eye than eye drops, and also to improve eye drop adherence by reducing the number of times eye drops are administered. (登録商標) It is also expected that the drug will have the same or better therapeutic effect on dry eye as eye drops at a lower concentration.

[0253] Furthermore, the composition is expected to exhibit high cell viability, be highly safe for the corneal and conjunctival epithelium, exhibit no nerve irritation, and improve the comfort of eye drops when applied.

[0254] Furthermore, even if the composition contains a silver salt, the silver salt is stable and exhibits excellent preservative effectiveness.

Claims

1. An aqueous ophthalmic composition comprising diquafosol or a salt thereof and polyvinylpyrrolidone.

2. The aqueous ophthalmic composition of claim 1 , further comprising a silver salt.

3. The aqueous ophthalmic composition of claim 2 , wherein the silver salt comprises silver nitrate.

4. The aqueous ophthalmic composition according to any one of claims 1 to 3, for preventing or treating dry eye.

5. 5. The aqueous ophthalmic composition of claim 4, comprising diquafosol sodium at a concentration of 1 to 5% (w / v) and polyvinylpyrrolidone having a K value of greater than 30 and less than or equal to 120.

6. 5. The aqueous ophthalmic composition of claim 4, comprising diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of greater than 30 and less than or equal to 120.

7. 5. The aqueous ophthalmic composition according to claim 4, comprising diquafosol sodium at a concentration of 1 to 5% (w / v) and having a viscosity of 1.5 to 30 mPa·s at 25°C.

8. 5. The aqueous ophthalmic composition according to claim 4, comprising diquafosol sodium at a concentration of 3% (w / v) and having a viscosity of 1.5 to 30 mPa·s at 25°C.

9. 9. The aqueous ophthalmic composition according to claim 5, which is administered by instillation into the eye two to four times a day.

10. 9. The aqueous ophthalmic composition according to claim 5, which is administered by instillation into the eye three times a day.

11. 11. The aqueous ophthalmic composition according to claim 9 or 10, which is administered by instillation into the eye in an amount of 1 to 2 drops at a time.

12. 10. An ophthalmic medicinal product comprising 0.1 to 1 mL of the aqueous ophthalmic composition according to claim 1 filled in a unit dose eye dropper container.

13. 10. An ophthalmologist's medicinal product, comprising 0.3 to 0.5 mL of the aqueous ophthalmic composition according to claim 1 filled in a unit dose eye dropper container.

14. 4. An ophthalmic medicinal product comprising 1 to 10 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 filled in a multi-dose eye dropper container.

15. An ophthalmic medicinal product, comprising 5 mL of the aqueous ophthalmic composition according to any one of claims 1 to 3 packed in a multi-dose eye dropper container.

16. An ophthalmic medicinal product, comprising 1 to 10 mL of the aqueous ophthalmic composition according to claim 1 filled in a PFMD container.

17. 13. An ophthalmic medicinal product comprising 5 mL of the aqueous ophthalmic composition of claim 1 packed in a PFMD container.

18. An ophthalmic medicinal product according to any one of claims 12 to 17 for the prevention or treatment of dry eye.

19. 20. The ophthalmic medicinal product of claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium in a concentration of 1-5% (w / v) and polyvinylpyrrolidone having a K value of >30 to <120.

20. 20. The ophthalmic medicinal product of claim 18, wherein the aqueous ophthalmic composition contains diquafosol sodium in a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of >30 to <120.

21. 19. The ophthalmic medicinal product of claim 18, wherein the aqueous composition contains diquafosol sodium in a concentration of 1-5% (w / v) and has a viscosity of 1.5-30 mPa·s at 25°C.

22. 19. The ophthalmic medicinal product of claim 18, wherein the aqueous composition contains diquafosol sodium in a concentration of 3% (w / v) and has a viscosity of 1.5 to 30 mPa·s at 25°C.

23. 23. Ophthalmic medicinal product according to any one of claims 19 to 22, characterized in that it is intended to be administered by instillation into the eyes 2 to 4 times a day.

24. 23. Ophthalmic medicinal product according to any one of claims 19 to 22, characterized in that it is intended to be administered by eye drop three times a day.

25. The ophthalmic medicinal product according to claim 23 or 24, characterized in that it is administered by instillation into the eye in an amount of 1 to 2 drops at a time.

26. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 or more.

27. The aqueous ophthalmic composition of any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 17 to 120.

28. The aqueous ophthalmic composition according to any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of from more than 30 to 120.

29. The aqueous ophthalmic composition of any one of claims 1 to 4, comprising polyvinylpyrrolidone having a K value of 90.

30. The aqueous ophthalmic composition of any one of claims 1 to 11, wherein the concentration of the polyvinylpyrrolidone is 0.001% (w / v) or more.

31. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the diquafosol or a salt thereof has a concentration of 0.0001 to 10% (w / v).

32. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the diquafosol or a salt thereof has a concentration of 0.01 to 5% (w / v).

33. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the diquafosol or a salt thereof has a concentration of 1 to 5% (w / v).

34. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the diquafosol or a salt thereof has a concentration of 3% (w / v).

35. 12. The aqueous ophthalmic composition of claim 1, wherein the aqueous ophthalmic composition has a pH in the range of 6 to 8.

36. 12. The aqueous ophthalmic composition of claim 1, wherein the aqueous ophthalmic composition has a pH in the range of 7 to 8.

37. The aqueous ophthalmic composition according to any one of claims 1 to 11, wherein the aqueous ophthalmic composition is a sterile aqueous eye drop.

38. The aqueous ophthalmic composition according to any one of claims 1 to 11, which is storable at room temperature.

39. The aqueous ophthalmic composition according to any one of claims 1 to 6, wherein the aqueous ophthalmic composition has a viscosity of 1.5 to 30 mPa·s at 25°C.

40. The aqueous ophthalmic composition according to any one of claims 1 to 4, wherein the salt of diquafosol is diquafosol sodium.

41. 1. An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone having a K value of 90, and silver nitrate, the composition being administered in the form of 1 to 2 drops at a time, 2 to 4 times a day.

42. An aqueous ophthalmic composition for preventing or treating dry eye, comprising diquafosol sodium at a concentration of 3% (w / v), polyvinylpyrrolidone and silver nitrate, the composition being administered in the form of 1 to 2 drops at a time, 2 to 4 times a day, and having a viscosity of 3 to 30 mPa s at 25°C.

43. 43. The aqueous ophthalmic composition of claim 41 or 42, which is administered by instillation into the eye three times a day.

44. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising: a unit-dose type eye dropper container filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90; and wherein the aqueous ophthalmic composition is administered by instillation in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

45. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising: a unit-dose type eye dropper container filled with 0.1 to 1 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25° C. and is administered by instillation into the eye, 1 to 2 drops at a time, 2 to 4 times a day.

46. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a multi-dose eye dropper container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, wherein the aqueous ophthalmic composition is administered by instillation in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

47. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a multi-dose eye dropper container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone, wherein the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25° C. and is administered by instillation into the eye by 1 to 2 drops at a time, 2 to 4 times a day.

48. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a PFMD container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone having a K value of 90, the ophthalmologist's medicinal product being characterized in that the aqueous ophthalmic composition is administered by instillation into the eye in an amount of 1 to 2 drops at a time, 2 to 4 times a day.

49. An ophthalmologist's medicinal product for preventing or treating dry eye, comprising a PFMD container filled with 1 to 10 mL of an aqueous ophthalmic composition containing diquafosol sodium at a concentration of 3% (w / v) and polyvinylpyrrolidone, the ophthalmologist's medicinal product being characterized in that the aqueous ophthalmic composition has a viscosity of 3 to 30 mPa·s at 25° C. and is administered by instillation into the eye, 1 to 2 drops at a time, 2 to 4 times a day.

50. 50. Ophthalmic medicinal product according to any one of claims 44 to 49, characterized in that it is intended to be administered by instillation three times a day.

51. 48. The ophthalmic medicated product of claim 46 or 47, further comprising silver nitrate.

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